Histamine is a chemical messenger involved in various complex biological actions. When released, histamine interacts with specific macromolecular receptors on the cell surface or within a target cell to elicit changes in many different bodily functions. Various cell types including smooth muscle, blood cells, cells of the immune system, endocrine and exocrine cells as well as neurons respond to histamine by modulating the formation of intracellular signals, including of phosphatidylinositol, or adenylate cyclase. Evidence that histamine plays a role as a neurotransmitter was established by the mid-to-late 1970's (Schwartz, 1975) Life Sci. 17:503-518. Immunohistochemical studies identified histaminergic cell bodies in the tuberomammillary nucleus of the posterior hypothalamus with widespread projections in the dicencephalon and telencephalon (Inagaki et al., 1998) J. Comp. Neurol. 273:283-300.
Two histamine receptors (H1 and H2) were reported to mediate the biochemical actions of histamine on neurons. More recently, studies have demonstrated the existence of a third subtype of histamine receptor, the histamine H3 receptor (Schwartz et al., 1986) TIPS 8: 24-28. Various studies have now demonstrated that histamine H3 receptors are found on the histaminergic nerve terminals in the brains of several species, including man (Arrang et al., 1983) Nature 302: 832-837. The H3 receptor found on the histaminergic nerve terminal was defined as an autoreceptor and could intimately control the amount of histamine released from the neurons. Histamine, the natural compound, was capable of stimulating this autoreceptor but testing of known H1 and H2 receptor agonists and antagonists suggested that the H3 receptor has a distinct pharmacological profile. Further, H3 receptors have been identified on cholinergic, serotonergic, glutamatergic and monoamine nerve terminals in the peripheral nervous system (PNS) and central nervous system including the cerebral cortex and cerebral vessels. These observations suggest that H3 receptors are uniquely located to modulate histamine as well as other neurotransmitter release, and compounds that bind H3 receptors could be important mediators of neuronal activity.
As stated, CNS histaminergic cell bodies are found in the magnocellular nuclei of the hypothalamic mammillary region and these neurons project diffusely to large areas of the forebrain. The presence of histaminergic cell bodies in the tuberomammillary nucleus of the posterior hypothalamus, a brain area involved in the maintenance of wakefulness, and their projections to the cerebral cortex suggest a role in modulating the arousal state or sleep-wake cycle. The histaminergic projection to many limbic structures such as the hippocampal formation and the amygdaloid complex suggest roles in functions such as autonomic regulation, control of emotions and motivated behaviors, and memory processes.
The concept that histamine is important for the state of arousal, as suggested by the location of histaminergic pathways, is supported by other types of evidence. Lesions of the posterior hypothalamus are well known to produce sleep. Neurochemical and electrophysiological studies have also indicated that the activity of histaminergic neurons is maximal during periods of wakefulness and is suppressed by barbiturates and other hypnotics. Intraventricular histamine induces the appearances of an arousal EEG pattern in rabbits and increased spontaneous locomotor activity, grooming and exploratory behavior in both saline and pentobarbital-treated rats.
In contrast, a highly selective inhibitor of histidine decarboxylase, the sole enzyme responsible for histamine synthesis, has been shown to impair waking in rats. These data support the hypothesis that histamine may function in modulating behavioral arousal. The role of the H3 receptor in sleep-waking parameters has been demonstrated (Lin et al., 1990) Brain Res. 592: 325-330. Oral administration of RAMHA, a H3 agonist, caused a significant increase in deep slow wave sleep in the cat. Conversely, thioperamide, a H3 antagonist/inverse agonist, enhanced wakefulness in a dose-dependent fashion. Thioperamide has also been shown to increase wakefulness and decrease slow-wave and REM sleep in rats. These findings are consistent with in vivo studies demonstrating that thioperamide caused an increase in synthesis and release of histamine. Together, these data demonstrate that selective H3 antagonists or inverse agonists may be useful in the treatment of arousal states and sleep disorders.
Serotonin, histamine, and acetylcholine have all been demonstrated to be diminished in the Alzheimer's (AD) brain. The histamine H3 receptor has been demonstrated to regulate the release of each of these neurotransmitters. An H3 receptor antagonist or inverse agonist would therefore be expected to increase the release of these neurotransmitters in the brain. Since histamine has been demonstrated to be important in arousal and vigilance, H3 receptor antagonists or inverse agonists might enhance arousal and vigilance via increasing levels of neurotransmitter release and thereby improve cognition. Thus, the use of compounds that bind the use of H3 receptor in AD, attention deficit disorders (ADD), age-related memory dysfunction and other cognitive disorders would be supported.
H3 receptor agonists, antagonists or inverse agonists may be useful in treating several other CNS disorders. It has been suggested that histamine may be involved in cerebral circulation, energy metabolism, and hypothalmic hormone secretion. For example, H3 receptor agonists, antagonists or inverse agonists have been demonstrated to affect food intake and body weight gain in rodents. Recent evidence has indicated the possible use of H3 agonists, antagonists or inverse agonists in the treatment of epilepsy. Work has demonstrated an inverse correlation between the duration of clonic convulsions and brain histamine levels. Thioperamide was also shown to significantly and dose-dependently decrease the durations of every convulsive phase after electrically-induced convulsions and increase the electroconvulsive threshold. For examples of therapeutical uses of H3 receptor agonists, inverse agonists or antagonists, see U.S. Pat. No. 6,316,475 or WO 03050099A1.
In spite of their low density, H3 receptor binding sites can be detected outside the brain. Several studies have revealed the presence of H3 heteroreceptors in the gastrointestinal tract, as well as upon neurons of the respiratory tract. Accordingly, an H3 receptor binding compound may be useful in the treatment of diseases and conditions such as asthma, rhinitis, airway congestion, inflammation, hyper and hypo motility and acid secretion of the gastrointestinal tract. Peripheral or central blockage of H3 receptors may also contribute to changes in blood pressure, heart rate and cardiovascular output and could be used in the treatment of cardiovascular diseases, and in the treatment of diseases or conditions such as obesity, migraine, inflammation, motion sickness, pain, ADHD, dementia, depression, Parkinson's disease, schizophrenia, epilepsy, narcolepsy, acute myocardial infarction and asthma.
Various pyrazole derivatives are disclosed in WO 03/024935; WO 03/095430; WO 89/03385; WO 93/23036; EP 0178035; and EP 0647629. For example, both WO 03/024935 and WO 03/095430 disclose certain substituted pyrazolyl compounds for treatment of inflammation. WO 00/19994 and WO 98/27061 disclose various cyclic compounds which may have a spectrum of agonist/antagonist properties.